The phosphatidylinositol (PI) 3-kinase (PI3K) pathway plays a central role in regulating many biological processes, including survival and proliferation, through the generation of the potent second messenger, PI-3,4,5-P3 (PIP3). This phospholipid is present at low levels in the plasma membrane of unstimulated cells but is rapidly synthesized from phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) by PI3K in response to a diverse array of extracellular stimuli. This transiently generated PIP3 initiates a cascade of downstream signaling pathways and attracts pleckstrin homology (PH) domain-containing proteins, such as Akt (also known as protein kinase B (PKB)), that regulate cellular activation, proliferation or survival, depending on the cell type and stimulus. Activation of the PI3K/Akt pathway has been linked with resistance to chemotherapeutic drugs and to radiation, and its down regulation via PI3K inhibitors lowers the resistance of tumour cell lines to various types of therapy.
Cellular levels of PIP3 are normally tightly regulated by both PI3K and the lipid phosphatases SHIP, SHIP2, and PTEN. The importance of lipid phosphatases to cellular homeostasis is underscored by the loss of activity or expression of these enzymes in human inflammatory diseases and in cancer. For example, to ensure that activation of the PI3K pathway is appropriately suppressed/terminated, the ubiquitously expressed tumour suppressor PTEN hydrolyzes PIP3 to PI-4,5-P2 while the hemopoietic restricted SH2-containing inositol-5′-phosphatase 1 (SHIP1), stem cell SHIP (sSHIP) (which is transcribed from a promoter between exons 5 and 6 of the SHIP gene and is expressed in embryonic stem (ES) cells and co-expressed, albeit at low levels, with SHIP1 in HSCs), and the more widely expressed SHIP2, break it down to PI-3,4-P2. Within non-hemopoietic cells, PTEN and SHIP2 appear to be the key enzymes that keep PIP3 levels suppressed while in hemopoietic cells, SHIP1 is the central player. SHIP1 (also known as SHIP), has been implicated as a negative regulator of proliferation/survival, differentiation and end cell activation in hemopoietic cells by translocating to membranes following extracellular stimulation and hydrolysation of PIP3 to PI-3,4-P2.